Targeting the oxidative microenvironment with a tannic acid-modified manganese dioxide nanozyme loaded with Honokiol nanoplatform to activate sirtuin 3-mediated deacetylation for alleviating cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion injury (CIRI) is a major contributor to neurological dysfunction following stroke, with oxidative stress (OS) and mitochondrial dysfunction identified as key pathological mechanisms. To enable precise and efficient therapeutic intervention, we developed a redox-responsive smart nanoplatform, tannic acid-modified manganese dioxide nanozyme loaded with honokiol (MnO₂@TA@HNK), for the targeted delivery of Honokiol (HNK), a known Sirtuin 3 (SIRT3) activator, to enhance antioxidant defense pathways. Near-infrared fluorescence imaging and tissue distribution analyses confirmed the platform's selective accumulation in ischemic brain regions. Behavioral assessments and 2,3,5-Triphenyltetrazolium chloride (TTC) staining demonstrated that this nanoplatform significantly reduced infarct volume and improved neurological outcomes. Integrated multi-omics analysis revealed that the therapeutic effects are mediated through activation of the SIRT3/nuclear factor erythroid 2-related factor 2 (Nrf2)/Superoxide Dismutase 2 (SOD2) axis, promoting redox homeostasis. Furthermore, molecular docking and Co-Immunoprecipitation (Co-IP) experiments validated that this mechanism is dependent on SIRT3-mediated deacetylation. This study provides the first comprehensive elucidation of the synergistic regulation of mitochondrial antioxidant defenses via a nanozyme-co-delivered small molecule, offering a novel nanotherapeutic strategy for the treatment of CIRI.